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stoichiometric_steve
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Aromatic iodinations
Synthesis of 3,5-diiodo-4-methoxyphenethylamine. Jatzkewitz, Horst; Noeske, Hans Dietrich. Univ. Tubingen, Germany.
Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie (1951), 287 43-6. CODEN: HSZPAZ ISSN: 0018-4888. Journal language unavailable. CAN
49:4568 AN 1955:4568 CAPLUS
Abstract
The synthesis of 3,5-diiodo-4-methoxyphenethylamine (I) is described. I is used to study the effect of biogenic amines on the action of mescaline.
To 14 g. tyramine-HCl in 23 cc. H2O and 46 cc. N NaOH, 11.8 g. iodine in alk. KI soln. (contg. 20 g. KI, 160 cc. H2O, and 46 cc. N NaOH) is added
dropwise with stirring, maintaining const. alky. The soln. is filtered and acidified with excess H2SO3, giving 12 g. crude 3,5-diiodotyramine-HI
(II), yellow leaves (from H2O) m. 232-4¡ (decompn.). II (12 g.) treated with the calcd. amt. of hot Na2CO3 soln. gives 6 g. free base (III), pale
yellow, m. 188-90¡. III (2 g.) boiled 10 s. with 5 cc. Ac2O and dild. with H2O gives 1.75 g. N-acetyl-3,5-diiodotyramine (IV), colorless plates, m.
139-40¡. IV (6 g.) (crude) in THF is methylated with 60 cc. ethereal CH2N2 dild. with 40 cc. CHCl3, washed twice with 5% NaOH and H2O, dried and the
solvent removed, giving 5.2 g. N-acetyl-3,5-diiodo-4-methoxyphenethylamine (V), needles, m. 138-40¡. V 3.8 g. is refluxed 5 h. with 19 cc. HCO2H, 14
cc. HCl, and 14 cc. H2O., evapd. in vacuo and dried with EtOH and C6H6, the residue extd. with three 15 cc.-portions of abs. C6H6 gives on evapn. of
the solvent 3.4 g. crude I.HCl. The pure compd. m. 213-15¡. The salt dried in Et2O over anhyd. K2CO3, on removal of solvent and crystn. from petr.
ether gives I, colorless leaflets, loses its crystal structure at 41-3¡, and m. 55-7¡.
- - - -
Now the question:
In the preparation of iodinated arylalkylamines, protection of the amine moiety is usually applied as to prevent formation of halo-amines. How come
this does apparentl not happen in the above procedure?
Is anybody aware if iodine (I2 or I+) will react with arylalkylamides to produce iodoamides?
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panziandi
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I posted a paper on the use of I2 / CrO3 in the anhydrous system AcOH/Ac2O for iodination and di-iodination of arenes. UTFSE but the paper is
uploaded, it may use examples of protected arylamines not too sure.
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chemrox
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Iodine is the least reactive of the halogens and the attacking species is something other than polarized I2. In the example given it may be ISO3
formed in situ.
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Nicodem
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| Quote: | Originally posted by stoichiometric_steve
In the preparation of iodinated arylalkylamines, protection of the amine moiety is usually applied as to prevent formation of halo-amines. How come
this does apparentl not happen in the above procedure?
Is anybody aware if iodine (I2 or I+) will react with arylalkylamides to produce iodoamides? |
In your example of a iodination the nucleophile is a phenoxide which reacts relatively easily with all iodinating species in the
reaction mixture (I<sub>2</sub>, I<sub>3</sub><sup>-</sup> and R-NHI). The amine protection is necessary when the
N-iodoamino group decomposes under the reaction conditions because unable to react any available nucleophile (for example, if you would want
to iodinate O-methyltyramine, etc.).
In my opinion, in the presence of excess iodide: R-CH<sub>2</sub>-NHI + 2I<sup>-</sup> <=>
R-CH<sub>2</sub>-NH<sub>2</sub> + I<sub>3</sub><sup>-</sup> is considerably faster than
R-CH<sub>2</sub>-NHI => R-CH=NH<sub>2</sub><sup>+</sup> + I<sup>-</sup> .
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solo
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Reference Information Quoted
The Direct Iodination of Arenes with Chromium (VI) Oxide as the Oxidant.
Lulinski, P. Skulski, L.
Bull. Chem. Soc. Jpn1997, 70, 1665-1669
https://sciencemadness.org/talk/viewthread.php?tid=11033&...
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stoichiometric_steve
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i'm not quite sure if an unprotected amine would survive CrO3, not to mention the environental/health risk with Cr based reagents.
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chemrox
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In any case the method cited did not use CrO3 or the acidic conditions that were part of that method. I didn't spot the tyramine + OH- =>
phenoxide which should have jumped out of the page. As I understand this the phenoxide reacts with any I species much faster than the amino group
would. This makes sense. @Steve: what health risk? you wear gloves in the lab don't you?
[Edited on 2-12-2008 by chemrox]
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harrydrez
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| Quote: | Originally posted by stoichiometric_steve
i'm not quite sure if an unprotected amine would survive CrO3, not to mention the environental/health risk with Cr based reagents.
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Hex chrome is some nasty stuff, definitely reduce it to the trivalent state before disposing of it if nothing else.
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DJF90
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I think he's more worried about working with it in the hexavalent oxidation state. Reduction before disposal is expected. Its not that bad, as with
every other chemical in the lab so long as you wear gloves and glasses, and use common sense, your exposure to it should be minimal. Handle in a hood
if you're really worried about it.
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chemrox
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Hex chrome is nasty stuff if dumped on the ground. I hope we're all above dumping our waste out the back door!
"When you let the dumbasses vote you end up with populism followed by autocracy and getting back is a bitch." Plato (sort of)
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panziandi
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CrO3 is quite a powerful oxidising agent and is a category 2 carcinogen (IIRC) and is dangerous for the environment.
I have performed iodinations using the I2/CrO3 system in acetic anhydride/acid solution with a small quantity of H2SO4 for iodination of several
compounds. I have not tried it with compounds containing an amine group. If I was, I would protect the amine by forming the acetamide by treating with
acetic anhydride. Then I would take that solution (without isolation of the derivative) and perform the iodination with I2/CrO3. The reaction is quite
nice and most of the CrO3 is reduced to Cr3+. When isolating the product I would treat it first with a little metabisulphite or something similar to
remove the excess Cr6+ then under basic conditions free-base the product and extract into a suitable solvent (likely diethyl ether). I think the
danger of Cr6+ comes from inhalation or ingestion, or skin contact with CrO3 will result in painful burns. There will be no Cr6+ in your product I'm
positive and anyhow, even if there was I'm sure you wouldn't be consuming it :p
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vulture
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Instead of using CrO3 you might consider using KIO3 or KIO4. No nasty Cr6+.
One shouldn't accept or resort to the mutilation of science to appease the mentally impaired.
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stoichiometric_steve
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What i meant about the Cr(VI) was that i dont like to work with reagents that aren't too easy to dispose of. Other than that, i dont give a shit about
teh chrome, sure i wear gloves n all
If acetylation provides enough protection from the reaction of Iodine with nitrogens, then i'm fine with iodination using I2/Ag(I) salts in MeOH.
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chemrox
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I got curious about the relative reactivities of the halogens and went to another PEA synthesis. Two in fact. Thanks to Dr. Shulgin I was able to
compare 2,5-dimethoxy-4-iodo-PEA with 4-bromo-2,5-dimethoxy-PEA. In the first case I-Cl was used for the iodination and the amine was protected via
the phthalimide. In the second case the amine wasn't protected and elemental Br2 was used for the halogenation. My chemistry isn't developed enough
to explain these facts right off the bat and I would appreciate anyone who can weighing in on this.
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stoichiometric_steve
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| Quote: | Originally posted by Nicodem
In my opinion, in the presence of excess iodide: R-CH<sub>2</sub>-NHI + 2I<sup>-</sup> <=>
R-CH<sub>2</sub>-NH<sub>2</sub> + I<sub>3</sub><sup>-</sup> is considerably faster than
R-CH<sub>2</sub>-NHI => R-CH=NH<sub>2</sub><sup>+</sup> + I<sup>-</sup>. |
isn't it quite the other way around? take 2,5-Dimethoxyphenethylamine for a prominent example. the lone electron pair appears much more reactive to me
than a weakly polarized C-H bond on the phenyl ring.
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Nicodem
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2,5-Dimethoxyphenethylamine is not a phenoxide! The electrophile in such a substrate must atack the neutral Pi-system which is only weakly
nucleophilic, regardless of the +M effect of the methoxy groups. Comparing the nucleophilicity of such a system with that of a phenoxide ion is like
comparing apples and tomatoes. In a phenoxide ion the negative charge is delocalized in the Pi-system making it many, many magnitudes more
nucleophilic as well as a bidentate nucleophile (there can be both, the O- or C-attack by the electrophile, but in the case of
iodination the O-attack is reversible and thus irrelevant for the reaction outcome).
Just to show the difference in the nucleophilicity:
- the nucleophilicity index N of anisol (PhOMe) is -1.18 (ref)
- the nucleophilicity index N of the phenoxide should be from 10 to 17 (I could not found the exact empirical value, but it should be there about the
same range as alkoxides, hydroxide and amines)
Note that this is a logarithmic empirical index and thus it indicates a difference in reactivity in the range of 10<sup>9</sup> to
10<sup>16</sup>. As a practical example, consider that with methyl bromide, the phenoxide ion reacts rapidly even at room temperature,
while anisole does not even if heated.
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unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
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chemrox
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Since no one did, I'm going to pose an answer to my own question. In the case of bromination, it's a free radical reaction with Br. acting as the
electrophile. In the iodination the elctrophile is I+ which would react with the lone pair on the amine. (I edited to add this) However it seems
like this would make the quaternary ammonium salt that could be converted back to the amine with base so why the phthalimide?
[Edited on 3-12-2008 by chemrox]
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smuv
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Under acidic conditions of the bromination the amine is non-nucleophilic as R-NH4+. Even if the N-haloamine is transiently produced in the weakly
acidic medium it likely simply serves as a source of Br+ in the bromination, which regenerates the amine again. In order for amines to do truly dirty
thing with halogens basic conditions are necessary.
The bromination should not be a free radical process. If you brominated in acetic acid the likely brominating species is AcOBr
AcOH + Br2 <--> AcOBr + HBr
AcOBr is a good source of Br+, and for activated aromatics gets the job done.
[Edited on 12-3-2008 by smuv]
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chemrox
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ahh- IC yes he used acetic acid not Fe, thanks. But why the protecting group for the iodination?
[Edited on 3-12-2008 by chemrox]
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Nicodem
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| Quote: | Originally posted by chemrox
ahh- IC yes he used acetic acid not Fe, thanks. But why the protecting group for the iodination? |
This was already explained. N-Iodoamines decompose easily, particularly in acidic media where they get protonated to
R-NH<sub>2</sub>I<sup>+</sup>. This is unlike bromo- and chloroamines which are much less sensitive to acids, but are
sensitive toward bases (due to the easy E2 reaction yielding iminium halides). See the N-X bond strength enthalpies, p-orbitals overlap ease due to
element period, and electronegativity difference between N and X = F, Cl, Br and I for understanding the polarisation of the bond; all factors from
which the different properties originate in the first place.
To take this comparison further, compare the shock sensitivity for NI<sub>3</sub>, NBr<sub>3</sub>,
NCl<sub>3</sub> and NF<sub>3</sub>. Actually NI<sub>3</sub> does not even exist as a discrete compound - as far as
I know only its Lewis complex with NH<sub>3</sub> can be isolated, at least for the time it takes to blow up.
| Quote: | Originally posted by chemrox
In the case of bromination, it's a free radical reaction with Br. acting as the electrophile. |
It is fanny how you managed to make a claim and then deny it in the same sentence. 
Electrophilic aromatic substitutions are polar reactions. They do not involve any radical mechanism - that's why they are called "electrophilic".
Attacks from radicals on aromatic systems rarely lead to substitution since this would require an radical addition/oxidation mechanism. For example,
radical chlorination of benzene never gives chlorobenzene, it gives a mixture of some diastereomers of 1,2,3,4,5,6-hexachlorocyclohexane instead (this
is the schoolbook example thought to undergraduates on what is the difference between polar and radical reactions on aromatics). On the other hand,
addition of carboradicals on benzene in the presence of a suitable single electron oxidant like Mn(III), Ce(IV), Ag(II), etc., can lead to
substitution reactions since the intermediate delocalized radical formed by the radical adding on the Pi-system gets oxidized to a carbocation by a
SET mechanism and this "rearomatizes" by eliminating a proton.
[Edited on 4/12/2008 by Nicodem]
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
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stoichiometric_steve
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| Quote: | | Originally posted by NicodemN-Iodoamines decompose easily, particularly in acidic media where they get protonated to
R-NH<sub>2</sub>I<sup>+</sup>. |
I'm not sure how/if this is meant to explain the need for protection of the amine. If the iodoamine decomposes more easily, does it decompose to the
iminium salt or -NH2 and I<sub>3</sub><sup>-</sup>?
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chemrox
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"It is fanny how you managed to make a claim and then deny it in the same sentence.
Electrophilic aromatic substitutions are polar reactions. They do not involve any radical mechanism "
Yeah I caught that a little late.... I had two ideas going at the same time; polarized Br-Br and Br. which would only exist in the presence of an
initiator like Fe. I envy your work environment. I work by myself and the only chemistry interraction I get is here.
"When you let the dumbasses vote you end up with populism followed by autocracy and getting back is a bitch." Plato (sort of)
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Nicodem
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| Quote: | Originally posted by stoichiometric_steve
| Quote: | | Originally posted by NicodemN-Iodoamines decompose easily, particularly in acidic media where they get protonated to
R-NH<sub>2</sub>I<sup>+</sup>. |
I'm not sure how/if this is meant to explain the need for protection of the amine. If the iodoamine decomposes more easily, does it decompose to the
iminium salt or -NH2 and I<sub>3</sub><sup>-</sup>? |
With "decomposition" I meant decomposition and not regeneration. I do not know the mechanism of N-iodoamines decomposition, but I do know it is not a
simple elimination like in the case of N-chloro- or N-bromoamines (the reason why these later two are unstable under basic conditions). N-Iodoamines
appear to be more stable under mildly basic than acidic conditions (kind of logical given the polarisation of the N-I bond precludes the E2 pathway).
Furthermore, in the experimental example you gave in the first post, the N-iodoamine is not in a favourable equilibrium since part of the already
mentioned redox system:
R-NHI + 2I<sup>-</sup> + H<sub>2</sub>O <=> R-NH<sub>2</sub> +
I<sub>3</sub><sup>-</sup> + OH<sup>-</sup>
Besides, the reaction is basic all the time; the iodinating electrophile I<sub>3</sub><sup>-</sup> is consumed rapidly; and no
heating is required. I would estimate that practically no decomposition due to the N-iodoamine occurs under such conditions.
But again, this is a iodination of a phenoxide with I<sub>3</sub><sup>-</sup> which is something very different from
iodination of anisoles and other less nucleophilic Pi-systems where any amino group must be protected (except for some rare exceptions - I think the
I<sub>2</sub>/Ag<sub>2</sub>SO<sub>4</sub> system can be used on unprotected amines, but I'm not sure - check the
literature).
| Quote: | Originally posted by chemrox
Yeah I caught that a little late.... I had two ideas going at the same time; polarized Br-Br and Br. which would only exist in the presence of an
initiator like Fe. I envy your work environment. I work by myself and the only chemistry interraction I get is here. |
I'm not certain of what you mean by "Br. which would only exist in the presence of an initiator like Fe", but I'm pretty sure you mixed up something.
Maybe you meant that a bromine radical can not exist in the presence of a reducent like elemental iron. That would make more sense though I can't see
the relevance here.
Anyway, if you rely on the information you get on this forum rather than reading scientific books and papers, you can be sure you will never learn
much of anything reliable or comprehensive regarding chemistry.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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stoichiometric_steve
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| Quote: | Originally posted by Nicodem
I think the I<sub>2</sub>/Ag<sub>2</sub>SO<sub>4</sub> system can be used on unprotected amines, but I'm not sure
- check the literature |
I've been SciFinding high and low, and i couldn't dig up any useful information on that, so i came here to ask. This is apparently a not-too-well
researched field of the art...
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Barium
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Tet. Lett., 1993, Vol. 34, No. 39, pp. 6223-6224
Iodination of various unprotected amines with iodine and silver sulfate
[Edited on 5-12-2008 by Barium]
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